bims-drudre 2022-09-25 papers

bims-drudre

Biomed News

on Targeted drug delivery and programmed release mechanisms

Issue of 2022‒09‒25
eighteen papers selected by
Ceren Kimna
Technical University of Munich

A Universal Chemotactic Targeted Delivery Strategy for Inflammatory Diseases.
Nanoparticle-modified microrobots for in vivo antibiotic delivery to treat acute bacterial pneumonia.
Kinetically Programming Copolymerization-like Coassembly of Multicomponent Nanoparticles with DNA.
Nanomaterials Mediated Co-Stimulation of toll-like Receptors and CD40 for Antitumor Immunity.
Scavenger receptor-targeted plaque delivery of microRNA-coated nanoparticles for alleviating atherosclerosis.
Cell-derived Vesicles for the Nanoparticles' Coating: Biomimetic Approaches for Enhanced Blood Circulation and Cancer Therapy.
Tuning the Dynamics of Viral Factories-Inspired Compartments Formed by Peptide-RNA Liquid-Liquid Phase Separation.
Oral Nanomotor-Enabled Mucus Traverse and Tumor Penetration for Targeted Chemo-Sono-Immunotherapy against Colon Cancer.
Thermoresponsive and Injectable Hydrogel for Tissue Agnostic Regeneration.
Biomimetic Polymeric Nanoparticle-Mediated Chemotherapy Potentiates Enhanced Tumor Immunotherapy via Amplification of Endoplasmic Reticulum Stress and Mitochondrial Dysfunction.
Precision genome editing in the eye.
Printable Metal-Polymer Conductors for Local Drug Delivery.
Endocytosis-like DNA uptake by cell wall-deficient bacteria.
Design of smart aggregates: towards rapid clinical diagnosis of hyperlipidemia in human blood.
Spray drying siRNA-lipid nanoparticles for dry powder pulmonary delivery.
Payload distribution and capacity of mRNA lipid nanoparticles.
Nanomaterial-based encapsulation for controlled gastrointestinal delivery of viable probiotic bacteria.
Mucoadhesive carriers for oral drug delivery.

Adv Mater. 2022 Sep 19. e2206654

A Universal Chemotactic Targeted Delivery Strategy for Inflammatory Diseases.

Ting Li, Zhiyong Liu, Jinglei Hu, Lin Chen, Tiantian Chen, Qianqian Tang, Bixia Yu, Bo Zhao, Chun Mao, Mimi Wan.

  Above 50% of deaths can be attributed to chronic inflammatory diseases, thus the construction of drug delivery system based on effective interaction of inflammatory factors with chemotactic nanoparticles is meaningful. Herein, we propose a zwitterion-based artificial chemotactic nanomotor for universal precise targeting strategy in vivo, where the high level of reactive oxygen species (ROS) and inducible nitric oxide synthase (iNOS) in inflammatory sites are used as chemoattractants. And the multi-dimensional static models, dynamic models and in vivo models are established to evaluate chemotactic performance. Results show that the up-regulated ROS and iNOS can induce the chemotaxis of nanomotors to diseased tissues in inflammation-related disease models. Further, the mesoscale hydrodynamics simulations are performed to explain the chemotactic behavior of nanomotors. Such chemotactic delivery strategy is expected to improve the delivery efficiency and may be applicable to a variety of inflammatory diseases. This article is protected by copyright. All rights reserved.

Keywords:  Chemotaxis; Inducible nitric-oxide synthase; Nanomotors; Reactive oxide species; Targeted delivery

DOI:  https://doi.org/10.1002/adma.202206654
Nat Mater. 2022 Sep 22.

Nanoparticle-modified microrobots for in vivo antibiotic delivery to treat acute bacterial pneumonia.

Fangyu Zhang, Jia Zhuang, Zhengxing Li, Hua Gong, Berta Esteban-Fernández de Ávila, Yaou Duan, Qiangzhe Zhang, Jiarong Zhou, Lu Yin, Emil Karshalev, Weiwei Gao, Victor Nizet, Ronnie H Fang, Liangfang Zhang, Joseph Wang.

Bioinspired microrobots capable of actively moving in biological fluids have attracted considerable attention for biomedical applications because of their unique dynamic features that are otherwise difficult to achieve by their static counterparts. Here we use click chemistry to attach antibiotic-loaded neutrophil membrane-coated polymeric nanoparticles to natural microalgae, thus creating hybrid microrobots for the active delivery of antibiotics in the lungs in vivo. The microrobots show fast speed (>110 µm s-1) in simulated lung fluid and uniform distribution into deep lung tissues, low clearance by alveolar macrophages and superb tissue retention time (>2 days) after intratracheal administration to test animals. In a mouse model of acute Pseudomonas aeruginosa pneumonia, the microrobots effectively reduce bacterial burden and substantially lessen animal mortality, with negligible toxicity. Overall, these findings highlight the attractive functions of algae-nanoparticle hybrid microrobots for the active in vivo delivery of therapeutics to the lungs in intensive care unit settings.

DOI: https://doi.org/10.1038/s41563-022-01360-9
ACS Nano. 2022 Sep 21.

Kinetically Programming Copolymerization-like Coassembly of Multicomponent Nanoparticles with DNA.

Tianyun Cai, Shuochen Zhao, Jiaping Lin, Liangshun Zhang.

  Programmable coassembly of multicomponent nanoparticles (NPs) into heterostructures has the capability to build upon nanostructured metamaterials with enhanced complexity and diversity. However, a general understanding of how to manipulate the sequence-defined heterostructures using straightforward concepts and quantitatively predict the coassembly process remains unreached. Drawing inspiration from the synthetic concepts of molecular block copolymers is extremely beneficial to achieve controllable coassembly of NPs and access mesoscale structuring mechanisms. We herein report a general paradigm of kinetic pathway guidance for the controllable coassembly of bivalent DNA-functionalized NPs into regular block-copolymer-like heterostructures via the stepwise polymerization strategy. By quantifying the coassembly kinetics and structural statistics, it is demonstrated that the coassembly of multicomponent NPs, through directing the specific pathways of prepolymer intermediates, follows the step-growth copolymerization mechanism. Meanwhile, a quantitative model is developed to predict the growth kinetics and outcomes of heterostructures, all controlled by the designed elements of the coassembly system. Furthermore, the stepwise polymerization strategy can be generalized to build upon a great variety of regular nanopolymers with complex architectures, such as multiblock terpolymers and ladder copolymers. Our theoretical and simulation results provide fundamental insights on quantitative predictions of the coassembly kinetics and coassembled outcomes, which can aid in realizing a diverse set of supramolecular DNA materials by the rational design of kinetic pathways.

Keywords:  Block copolymers; Coarse-grained molecular dynamics; DNA-functionalized nanoparticles; Programmable coassembly; Step-growth copolymerization; Supramolecular polymerization

DOI:  https://doi.org/10.1021/acsnano.2c02867
Adv Mater. 2022 Sep 19. e2207486

Nanomaterials Mediated Co-Stimulation of toll-like Receptors and CD40 for Antitumor Immunity.

Jingyue Yan, Yuebao Zhang, Shi Du, Xucheng Hou, Wenqing Li, Chunxi Zeng, Chengxiang Zhang, Jeffrey Cheng, Binbin Deng, David W McComb, Weiyu Zhao, Yonger Xue, Diana D Kang, Xiaolin Cheng, Yizhou Dong.

  Toll-like Receptors (TLRs) and CD40 related-signaling pathways represent critical bridges between the innate and adaptive immune responses. Here, we develop an immunotherapy regimen that enables co-stimulation of TLR7/8 and CD40 mediated pathways. TLR7/8 agonist resiquimod (R848) derived amino lipids, RAL1 and RAL2, are synthesized and formulated into RAL-derived lipid nanoparticles (RAL-LNPs). The RAL2-LNPs show efficient CD40 mRNA delivery to DCs both in vitro (90.8 ± 2.7%) and in vivo (61.3 ± 16.4%). When combined with agonistic anti-CD40 antibody, this approach can produce effective antitumor activities in mouse melanoma tumor models, thereby suppressing tumor growth, prolonging mouse survival, and establishing antitumor memory immunity. Overall, RAL2-LNPs provide a novel platform towards cancer immunotherapy by integrating innate and adaptive immunity. This article is protected by copyright. All rights reserved.

Keywords:  CD40; immunotherapy; lipid nanoparticles; mRNA; resiquimod

DOI:  https://doi.org/10.1002/adma.202207486
Proc Natl Acad Sci U S A. 2022 Sep 27. 119(39): e2201443119

Scavenger receptor-targeted plaque delivery of microRNA-coated nanoparticles for alleviating atherosclerosis.

Qianqian Bai, Yu Xiao, Huiling Hong, Xiaoyun Cao, Lei Zhang, Ruifang Han, Leo Kit Cheung Lee, Evelyn Y Xue, Xiao Yu Tian, Chung Hang Jonathan Choi.

  Atherosclerosis treatments by gene regulation are garnering attention, yet delivery of gene cargoes to atherosclerotic plaques remains inefficient. Here, we demonstrate that assembly of therapeutic oligonucleotides into a three-dimensional spherical nucleic acid nanostructure improves their systemic delivery to the plaque and the treatment of atherosclerosis. This noncationic nanoparticle contains a shell of microRNA-146a oligonucleotides, which regulate the NF-κB pathway, for achieving transfection-free cellular entry. Upon an intravenous injection into apolipoprotein E knockout mice fed with a high-cholesterol diet, this nanoparticle naturally targets class A scavenger receptor on plaque macrophages and endothelial cells, contributing to elevated delivery to the plaques (∼1.2% of the injected dose). Repeated injections of the nanoparticle modulate genes related to immune response and vascular inflammation, leading to reduced and stabilized plaques but without inducing severe toxicity. Our nanoparticle offers a safe and effective treatment of atherosclerosis and reveals the promise of nucleic acid nanotechnology for cardiovascular disease.

Keywords:  atherosclerosis; cardiovascular disease; gene therapy; nanomedicine; nucleic acid nanotechnology

DOI:  https://doi.org/10.1073/pnas.2201443119
Adv Healthc Mater. 2022 Sep 19. e2201214

Cell-derived Vesicles for the Nanoparticles' Coating: Biomimetic Approaches for Enhanced Blood Circulation and Cancer Therapy.

Carolina F Rodrigues, Natanael Fernandes, Duarte de Melo-Diogo, Ilídio J Correia, André F Moreira.

  Cancer nanomedicines are designed to encapsulate different therapeutic agents, prevent their premature release, and deliver them specifically to cancer cells, due to their ability to preferentially accumulate in tumor tissue. However, after intravenous administration, nanoparticles immediately interact with biological components that facilitate their recognition by the immune system, being rapidly removed from circulation. Reports show that less than 1% of the administered nanoparticles effectively reach the tumor site. This suboptimal pharmacokinetic profile is pointed out as one of the main factors for the nanoparticles' sub-optimal therapeutic effectiveness and poor translation to the clinic. Therefore, an extended blood circulation time may be crucial to increase the nanoparticles' chances of being accumulated in the tumor and promote a site-specific delivery of therapeutic agents. For that purpose, the understanding of the forces that govern the nanoparticles' interaction with biological components and the impact of the physicochemical properties on the in vivo fate will allow the development of novel and more effective nanomedicines. Therefore, in this review, the nano-bio interactions are summarized. Moreover, the application of cell-derived vesicles for extending the blood circulation time and tumor accumulation is reviewed, focusing on the advantages and shortcomings of each cell source. This article is protected by copyright. All rights reserved.

Keywords:  Blood circulation; Cancer; Cell-derived vesicles; Nanoparticles; Protein corona; Stealthing

DOI:  https://doi.org/10.1002/adhm.202201214
Adv Mater. 2022 Sep 22. e2206371

Tuning the Dynamics of Viral Factories-Inspired Compartments Formed by Peptide-RNA Liquid-Liquid Phase Separation.

Itai Katzir, Elvira Haimov, Ayala Lampel.

  Viral factories are intracellular microcompartments formed by mammalian viruses in their host cells, and contain necessary machinery for viral genome replication, capsid assembly and maturation, thus serve as "factories" for formation of new viral particles. Recent evidence suggest that these compartments are formed by liquid-liquid phase separation (LLPS) of viral proteins and nucleic acids and present dynamic properties. Inspired by the remarkable functionalities of viral factories we designed dynamic compartments that are formed by complexation between a minimalistic, disordered peptide and RNA. By systematic studies using sequence variants we show that the material properties of the compartments can be modulated by changes to the peptide sequence, at a single amino acid level. Moreover, by taking this approach to the next step, we developed liquid compartments with light-induced tunable dynamics. Our results demonstrate that the material properties of liquid droplets can be temporally regulated by increasing peptide polarity and charge, and that these changes can be further utilized for controlled partitioning and release of payloads from the compartments. This article is protected by copyright. All rights reserved.

Keywords:  coacervates; liquid droplets; liquid-liquid phase separation; membraneless organelles; peptides; viral factories

DOI:  https://doi.org/10.1002/adma.202206371
Small. 2022 Sep 18. e2203466

Oral Nanomotor-Enabled Mucus Traverse and Tumor Penetration for Targeted Chemo-Sono-Immunotherapy against Colon Cancer.

Yingui Cao, Shengsheng Liu, Ya Ma, Lingli Ma, Menghang Zu, Jianfeng Sun, Fangyin Dai, Lian Duan, Bo Xiao.

  The therapeutic outcomes of oral nanomedicines against colon cancer are heavily compromised by their lack of specific penetration into the internal tumor, favorable anti-tumor activity, and activation of anti-tumor immunity. Herein, hydrogen peroxide (H2 O2 )/ultrasound (US)-driven mesoporous manganese oxide (MnOx )-based nanomotors are constructed by loading mitochondrial sonosensitizers into their mesoporous channels and orderly dual-functionalizing their surface with silk fibroin and chondroitin sulfate. The locomotory activities and tumor-targeting capacities of the resultant nanomotors (CS-ID@NMs) are greatly improved in the presence of H2 O2 and US irradiation, inducing efficient mucus-traversing and deep tumor penetration. The excess H2 O2 in the tumor microenvironment (TME) is decomposed into hydroxyl radicals and oxygen by an Mn2+ -mediated Fenton-like reaction, and the produced oxygen participates in sonodynamic therapy (SDT), yielding abundant singlet oxygen. The combined Mn2+ -mediated chemodynamic therapy and SDT cause effective ferropotosis of tumor cells and accelerate the release of tumor antigens. Importantly, animal experiments reveal that the treatment of combining oral hydrogel (chitosan/alginate)-embedding CS-ID@NMs and immune checkpoint inhibitors can simultaneously suppress the growth of primary and distal tumors through direct killing, reversion of immunosuppressive TME, and potentiation of systemic anti-tumor immunity, demonstrating that the CS-ID@NM-based platform is a robust oral system for synergistic treatment of colon cancer.

Keywords:  mucus traversing; nanomotors; oral administration; synergistic treatment; tumor penetration

DOI:  https://doi.org/10.1002/smll.202203466
Adv Healthc Mater. 2022 Sep 23. e2201714

Thermoresponsive and Injectable Hydrogel for Tissue Agnostic Regeneration.

Dax Calder, Ali Fathi, Farshad Oveissi, Simin Maleknia, Terence Abrams, Yiwei Wang, Joanneke Maitz, Kevin Hung-Yueh Tsai, Peter Maitz, Wojtek Chrzanowski, Ivan Canoy, Vivek Ashoka, Menon, Kenneth Lee, Benjamin J Ahern, Natasha E Lean, Dina M Silva, Paul M Young, Daniela Traini, Hui Xin Ong, Rasoul Seyed Mahmoud, Hossein Montazerian, Ali Khademhosseini, Fariba Dehghani.

  Injectable hydrogels can support the body's innate healing capability by providing a temporary matrix for host cell ingrowth and neovascularization. The clinical adoption of current injectable systems remains low due to their cumbersome preparation requirements, device malfunction, product dislodgment during administration and uncontrolled biological responses at the treatment site. To address these challenges, we engineered a fully synthetic and ready-to-use injectable biomaterial that forms an adhesive hydrogel that remains at the administration site regardless of defect anatomy. The product elicits a negligible local inflammatory response and fully resorbs into non-toxic components with minimal impact on internal organs. Preclinical animal studies confirmed that the engineered hydrogel upregulates the regeneration of both soft and hard tissues by providing a temporary matrix to support host cell ingrowth and neovascularization. In a pilot clinical trial, the engineered hydrogel was successfully administered to a socket site post tooth extraction and formed adhesive hydrogel that stabilized blood clot and supported soft and hard tissue regeneration. Accordingly, this injectable hydrogel exhibits high therapeutic potential and can be adopted to address multiple unmet needs in different clinical settings. This article is protected by copyright. All rights reserved.

Keywords:  injectable hydrogel; platform technology; regenerative medicine

DOI:  https://doi.org/10.1002/adhm.202201714
Adv Mater. 2022 Sep 20. e2206861

Biomimetic Polymeric Nanoparticle-Mediated Chemotherapy Potentiates Enhanced Tumor Immunotherapy via Amplification of Endoplasmic Reticulum Stress and Mitochondrial Dysfunction.

Yunqi Guo, Yu Fan, Zhiqiang Wang, Gaoming Li, Mengsi Zhan, Junli Gong, Jean-Pierre Majoral, Xiangyang Shi, Mingwu Shen.

  Construction of multifunctional nanoplatforms to elevate chemotherapeutic efficacy and induce long-term antitumor immunity still remains to be an extreme challenge. Herein, we report the design of an advanced redox-responsive nanomedicine formulation based on phosphorus dendrimer-copper(II) complexes (1G3 -Cu)- and toyocamycin (Toy)-loaded polymeric nanoparticles (GCT NPs) coated with cancer cell membranes (CM). The designed GCT@CM NPs with a size of 210 nm are stable under a physiological condition but are rapidly dissociated in the reductive tumor microenvironment to deplete glutathione and release drugs. The co-loading of 1G3 -Cu and Toy within the NPs causes significant tumor cell apoptosis and immunogenic cell death through 1G3 -Cu-induced mitochondrial dysfunction and Toy-mediated amplification of endoplasmic reticulum stress, respectively, thus effectively suppressing tumor growth, promoting dendritic cell maturation, and increasing tumor-infiltrating cytotoxic T lymphocytes. Likewise, the coated CM and the loaded 1G3 -Cu render the GCT@CM NPs with homotypic targeting and T1 -weighted magnetic resonance imaging of tumors, respectively. With the assistance of programmed cell death ligand 1 antibody, the GCT@CM NP-mediated chemotherapy can significantly potentiate tumor immunotherapy for effective inhibition of tumor recurrence and metastasis. The developed GCT@CM NPs hold a great potential for chemotherapy-potentiated immunotherapy of different tumor types through different mechanisms or synergies. This article is protected by copyright. All rights reserved.

Keywords:  chemotherapy-potentiated immunotherapy; immunogenic cell death; phosphorus dendrimers; redox-responsiveness; toyocamycin

DOI:  https://doi.org/10.1002/adma.202206861
Proc Natl Acad Sci U S A. 2022 Sep 27. 119(39): e2210104119

Precision genome editing in the eye.

Susie Suh, Elliot H Choi, Aditya Raguram, David R Liu, Krzysztof Palczewski.

  CRISPR-Cas-based genome editing technologies could, in principle, be used to treat a wide variety of inherited diseases, including genetic disorders of vision. Programmable CRISPR-Cas nucleases are effective tools for gene disruption, but they are poorly suited for precisely correcting pathogenic mutations in most therapeutic settings. Recently developed precision genome editing agents, including base editors and prime editors, have enabled precise gene correction and disease rescue in multiple preclinical models of genetic disorders. Additionally, new delivery technologies that transiently deliver precision genome editing agents in vivo offer minimized off-target editing and improved safety profiles. These improvements to precision genome editing and delivery technologies are expected to revolutionize the treatment of genetic disorders of vision and other diseases. In this Perspective, we describe current preclinical and clinical genome editing approaches for treating inherited retinal degenerative diseases, and we discuss important considerations that should be addressed as these approaches are translated into clinical practice.

Keywords:  eye; genome editing; retina; retinal degeneration

DOI:  https://doi.org/10.1073/pnas.2210104119
Nano Lett. 2022 Sep 19.

Printable Metal-Polymer Conductors for Local Drug Delivery.

Ning Ren, Chen Hang, Xiaoyan Liu, Xingyu Jiang.

  Safe and effective local drug delivery is challenging due to complex physiological barriers that limit the entry of drugs. Here, we report the metal-polymer conductors (MPCs) for local drug delivery via iontophoresis or electroporation. The MPCs are stretchable, conductive, and biocompatible. The flexible MPCs of different geometries are used both on a dry, flat surface (skin) and a moist, curved surface (cornea) with conformability. Conformal integration with the tissues enables good mechanical/electrical properties and realizes application of electrical voltage to the target areas for local drug delivery. By iontophoresis and electroporation, the MPCs achieve efficient delivery of doxorubicin and siRNA, leading to tumor regression and inhibition of corneal neovascularization, respectively. Our work presents an efficient strategy to harness the power of the MPCs to broaden the scope of local drug delivery to dry and wet organs with different surface topography.

Keywords:  corneal neovascularization; electroporation; iontophoresis; melanoma; metal−polymer conductors

DOI:  https://doi.org/10.1021/acs.nanolett.2c02548
Nat Commun. 2022 Sep 22. 13(1): 5524

Endocytosis-like DNA uptake by cell wall-deficient bacteria.

Renée Kapteijn, Shraddha Shitut, Dennis Aschmann, Le Zhang, Marit de Beer, Deniz Daviran, Rona Roverts, Anat Akiva, Gilles P van Wezel, Alexander Kros, Dennis Claessen.

Horizontal gene transfer in bacteria is widely believed to occur via conjugation, transduction and transformation. These mechanisms facilitate the passage of DNA across the protective cell wall using sophisticated machinery. Here, we report that cell wall-deficient bacteria can engulf DNA and other extracellular material via an endocytosis-like process. Specifically, we show that L-forms of the filamentous actinomycete Kitasatospora viridifaciens can take up plasmid DNA, polysaccharides (dextran) and 150-nm lipid nanoparticles. The process involves invagination of the cytoplasmic membrane, leading to formation of intracellular vesicles that encapsulate extracellular material. DNA uptake is not affected by deletion of genes homologous to comEC and comEA, which are required for natural transformation in other species. However, uptake is inhibited by sodium azide or incubation at 4 °C, suggesting the process is energy-dependent. The encapsulated materials are released into the cytoplasm upon degradation of the vesicle membrane. Given that cell wall-deficient bacteria are considered a model for early life forms, our work reveals a possible mechanism for primordial cells to acquire food or genetic material before invention of the bacterial cell wall.

DOI: https://doi.org/10.1038/s41467-022-33054-w
Adv Mater. 2022 Sep 22. e2207671

Design of smart aggregates: towards rapid clinical diagnosis of hyperlipidemia in human blood.

Feiyi Sun, Wei Zhao, Hanchen Shen, Ni Fan, Jianyu Zhang, Qingqing Liu, Changhuo Xu, Jiaming Luo, Mengying Zhao, Yuyang Chen, Kristy W K Lam, Xueqin Yang, Ryan T K Kwok, Jacky W Y Lam, Jianwei Sun, Hongfei Zhang, Ben Zhong Tang.

  Molecular aggregates with environmental responsive property are desired for their wide practical applications such as bio-probes. Here, we report a series of smart near-infrared (NIR) luminogens for hyperlipidemia (HLP) diagnosis. The aggregates of these molecules exhibit the twisted intramolecular charge transfer effect in aqueous medium, but aggregation-induced emission in high viscous medium due to the restriction of the intramolecular motion. We describe these aggregates, which can autonomously respond to different environments via switching of the aggregation state without changing their chemical structures, as "smart aggregates". Intriguingly, these luminogens demonstrate NIR-II and NIR-III luminescence with ultra-large Stokes shifts (> 950 nm). Both in vitro detection and in vivo imaging of HLP can be realized in a mouse model. Linear relationships exist between the emission intensity and multiple pathological parameters in blood samples of HLP patients. Thus, the design of smart aggregate facilitates rapid and accurate detection of HLP and provides a promising attempt in aggregate science. This article is protected by copyright. All rights reserved.

Keywords:  aggregation-induced emission; hyperlipidemia; near-infrared; stokes shift; twisted intramolecular charge transfer

DOI:  https://doi.org/10.1002/adma.202207671
J Control Release. 2022 Sep 17. pii: S0168-3659(22)00613-7. [Epub ahead of print]

Spray drying siRNA-lipid nanoparticles for dry powder pulmonary delivery.

Christoph M Zimmermann, Domizia Baldassi, Karen Chan, Nathan B P Adams, Alina Neumann, Diana Leidy Porras-Gonzalez, Xin Wei, Nikolaus Kneidinger, Mircea Gabriel Stoleriu, Gerald Burgstaller, Dominik Witzigmann, Paola Luciani, Olivia M Merkel.

  While all the siRNA drugs on the market target the liver, the lungs offer a variety of currently undruggable targets which could potentially be treated with RNA therapeutics. Hence, local, pulmonary delivery of RNA nanoparticles could finally enable delivery beyond the liver. The administration of RNA drugs via dry powder inhalers offers many advantages related to physical, chemical and microbial stability of RNA and nanosuspensions. The present study was therefore designed to test the feasibility of engineering spray dried lipid nanoparticle (LNP) powders. Spray drying was performed using 5% lactose solution (m/V), and the targets were set to obtain nanoparticle sizes after redispersion of spray-dried powders around 150 nm, a residual moisture level below 5%, and RNA loss below 15% at maintained RNA bioactivity. The LNPs consisted of an ionizable cationic lipid which is a sulfur-containing analog of DLin-MC3-DMA, a helper lipid, cholesterol, and PEG-DMG encapsulating siRNA. Prior to the spray drying, the latter process was simulated with a novel dual emission fluorescence spectroscopy method to preselect the highest possible drying temperature and excipient solution maintaining LNP integrity and stability. Through characterization of physicochemical and aerodynamic properties of the spray dried powders, administration criteria for delivery to the lower respiratory tract were fulfilled. Spray dried LNPs penetrated the lung mucus layer and maintained bioactivity for >90% protein downregulation with a confirmed safety profile in a lung adenocarcinoma cell line. Additionally, the spray dried LNPs successfully achieved up to 50% gene silencing of the house keeping gene GAPDH in ex vivo human precision-cut lung slices at without increasing cytokine levels. This study verifies the successful spray drying procedure of LNP-siRNA systems maintaining their integrity and mediating strong gene silencing efficiency on mRNA and protein levels both in vitro and ex vivo. The successful spray drying procedure of LNP-siRNA formulations in 5% lactose solution creates a novel siRNA-based therapy option to target respiratory diseases such as lung cancer, asthma, COPD, cystic fibrosis and viral infections.

Keywords:  Formulation screening; Human precision-cut lung slices; LNP; Lipid nanoparticles; Onpattro®; Pulmonary delivery; RNA therapeutics; Respiratory diseases; Spray drying; siRNA delivery

DOI:  https://doi.org/10.1016/j.jconrel.2022.09.021
Nat Commun. 2022 Sep 23. 13(1): 5561

Payload distribution and capacity of mRNA lipid nanoparticles.

Sixuan Li, Yizong Hu, Andrew Li, Jinghan Lin, Kuangwen Hsieh, Zachary Schneiderman, Pengfei Zhang, Yining Zhu, Chenhu Qiu, Efrosini Kokkoli, Tza-Huei Wang, Hai-Quan Mao.

Lipid nanoparticles (LNPs) are effective vehicles to deliver mRNA vaccines and therapeutics. It has been challenging to assess mRNA packaging characteristics in LNPs, including payload distribution and capacity, which are critical to understanding structure-property-function relationships for further carrier development. Here, we report a method based on the multi-laser cylindrical illumination confocal spectroscopy (CICS) technique to examine mRNA and lipid contents in LNP formulations at the single-nanoparticle level. By differentiating unencapsulated mRNAs, empty LNPs and mRNA-loaded LNPs via coincidence analysis of fluorescent tags on different LNP components, and quantitatively resolving single-mRNA fluorescence, we reveal that a commonly referenced benchmark formulation using DLin-MC3 as the ionizable lipid contains mostly 2 mRNAs per loaded LNP with a presence of 40%-80% empty LNPs depending on the assembly conditions. Systematic analysis of different formulations with control variables reveals a kinetically controlled assembly mechanism that governs the payload distribution and capacity in LNPs. These results form the foundation for a holistic understanding of the molecular assembly of mRNA LNPs.

DOI: https://doi.org/10.1038/s41467-022-33157-4
Nanoscale Adv. 2021 May 18. 3(10): 2699-2709

Nanomaterial-based encapsulation for controlled gastrointestinal delivery of viable probiotic bacteria.

Seyedehhamideh Razavi, Sajjad Janfaza, Nishat Tasnim, Deanna L Gibson, Mina Hoorfar.

Probiotics are microorganisms that have beneficial health effects when administered in adequate dosages. The oral administration of probiotic bacteria is widely considered beneficial for both intestinal as well as systemic health but its clinical efficacy is conflicted in the literature. This may at least in part be due to the loss of viability during gastrointestinal passage resulting in poor intestinal delivery. Microencapsulation technology has been proposed as a successful strategy to address this problem by maintaining the viability of probiotics, thereby improving their efficacy following oral administration. More recently, nanomaterials have demonstrated significant promise as encapsulation materials to improve probiotic encapsulation. The integration of nanotechnology with microencapsulation techniques can improve the controlled delivery of viable probiotic bacteria to the gut. The current review aims at summarizing the types of nanomaterials used for the microencapsulation of probiotics and showing how they can achieve the delivery and controlled release of probiotics at the site of action.

DOI: https://doi.org/10.1039/d0na00952k
J Control Release. 2022 Sep 15. pii: S0168-3659(22)00616-2. [Epub ahead of print]

Mucoadhesive carriers for oral drug delivery.

Raj Kumar, Tamanna Islam, Md Nurunnabi.

  Among the various dosage forms, oral medicine has extensive benefits including ease of administration and patients' compliance, over injectable, suppositories, ocular and nasal. Despite of extensive demand and emerging advantages, over 50% of therapeutic molecules are not available in oral form due to their physicochemical properties. More importantly, most of the biologics, proteins, peptide, and large molecular drugs are mostly available in injectable form. Conventional oral drug delivery system has limitation such as degradation and lack of stability within stomach due to presence of highly acidic gastric fluid, hinders their therapeutic efficacy and demand more frequent and higher dosing. Hence, formulation for controlled, sustained, and targeted drug delivery, need to be designed with feasibility to target the specific region of gastrointestinal (GI) tract such as stomach, small intestine, intestine lymphatic, and colon is challenging. Among various oral delivery approaches, mucoadhesive vehicles are promising and has potential for improving oral drug retention and controlled absorption to treat local diseases within the GI tract, as well systemic diseases. This review provides the overview about the challenges and opportunities to design mucoadhesive formulation for oral delivery of therapeutics in a way to target the specific region of the GI tract. Finally, we have concluded with future perspective and potential of mucoadhesive formulations for oral local and systemic delivery.

Keywords:  Gastric cancer; Inflammatory bowel disease; Mucoadhesive polymer; Oral delivery; Oral medicine

DOI:  https://doi.org/10.1016/j.jconrel.2022.09.024